Platelets play a critical role in the blood clotting mechanism. Depletion of platelets below a certain level results in thrombocytopenia, which can be triggered by a number of clinical conditions and disorders and can range from mild to life-threatening.
Thombocytopenia can be triggered by diseases and conditions affecting the bone marrow, where platelet precursors arise before entering the bloodstream; by diseases and conditions affecting the liver, which produces thrombopoietin, the hormone that stimulates the production of platelets; by sequestration of platelets; by increased destruction of platelets; and by a variety of other causes. In particular, thrombocytopenia is a common side effect of certain treatment regimens, such as cancer treatment regimens involving antineoplastic agents. Chemotherapy-induced or radiation-induced thrombocytopenia can result in delays in treatment and/or compel reductions in treatment dose, which in turn can result in reduced efficacy of the treatment.
Because severe thrombocytopenia puts a patient at risk of uncontrolled hemorrhage, development of safe and effective treatments for thrombocytopenia is highly desirable. In spite of the clear need for such treatments, however, very few such treatments exist. Attempts to develop a recombinant form of human thrombopoietin have proved unsuccessful. While a recombinant human thrombopoietin showed early promise, it showed a tendency to induce the development of auto-antibodies when tested in patients. Currently, standard therapy of thrombocytopenia, such as immune-mediated thrombocytopenia, can include treatment with corticosteroids, rituximab, and/or thrombopoietin receptor agonists, splenectomy, and platelet transfusions. However, each has drawbacks, including incomplete response, development of side effects to treatment, and risks attendant to any form of surgery. For chemotherapy-induced thrombocytopenia, only one therapeutic agent, interleukin-11, has proven sufficiently effective to merit regulatory approval, but is rarely prescribed by physicians because of the severity of its side effects. For radiation-induced thrombocytopenia, there is no approved therapeutic agent that attenuates the thrombocytopenia. Thus, there remains a significant need for agents that attenuate thrombocytopenias of varying etiology, including immune-mediated thrombocytopenias, drug-induced thrombocytopenias, especially chemotherapy-induced thrombocytopenia, and radiation-induced thrombocytopenia.
Neutrophils, also called polymorphonuclear leukocytes, are the most numerous of the blood cells known as granulocytes. Neutrophils, like other blood cells, are produced by the bone marrow. Neutrophils are an important component of natural immunity. When neutrophil levels fall below normal, a condition called neutropenia occurs, increasing the risk of infection. Neutropenia can arise from a number of different causes, ranging from congenital defects to viral infections, but a context in which neutropenia frequently occurs is as a side effect of a treatment regimen. Neutropenia is a common side effect in patients being treated for cancer with antineoplastic agents, putting patients at risk of developing serious and even life-threatening infections, and forcing delays in treatment and/or compelling reduction in treatment dose, resulting in reduced efficacy.
A variety of agents and therapies have been tested to combat neutropenia, with varying degrees of success. Administration of glucocorticoids, androgenic steroids, and vitamins to stimulate bone marrow to produce more neutrophils has not proved successful. At present, only two agents—granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)—are widely used to treat patients with severe neutropenia, most often after intensive cancer chemotherapy and/or bone marrow transplantation. These agents exhibit adverse effects such as bone pain, abnormalities of liver dysfunctions and pleural and pericardial effusions. Thus, there is a need for compounds that are safe and effective for treating neutropenia and promoting neutrophil production.